PROJECT SUMMARY/ABSTRACT Despite advances in precision oncology, cancer remains a leading cause of death around the world. Immunotherapies, including checkpoint blockade inhibitors and adoptive T cell therapy, are transforming cancer care and hold great promise in delivering cure for many cancer patients. Yet, only a proportion of patients responds to immunotherapy, and underlying factors are incompletely understood. Treatment success has been associated to the presence of tumor infiltrating lymphocytes (TILs) which lie at the heart of cancer immunotherapies. TILs abundance has also been associated with good clinical outcome in many different cancers, regardless of treatment. To date, most efforts to elucidate factors that contribute to the observed variability in immune response against cancers, and its associated clinical outcome, have focused on the role of tumor characteristics and the cancer genome. Very little attention has been paid to the role of germline genetic factors in the immune response to cancers, or clinical outcomes, and, therefore, their role is poorly understood. The overarching goal of this study is to identify germline genetic factors associated with tumor immune profile within and across solid tissue cancers, and to examine their role in colorectal cancer (CRC) risk and survival outcomes. To achieve this, we propose to leverage transcriptome data from primary, untreated solid tumors (n=8,578) and matched germline genome-wide single nucleotide variant data generated by The Cancer Genome Atlas (TCGA) project. Using state-of-the-art imputation reference panels and statistical algorithms, we will perform in silico genotyping of nearly all common variants, many rare variants with a minor allele frequency as low as 0.1% in the population, and human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) types. We propose to perform an agnostic genome-wide association study (GWAS) of TIL subpopulations in solid tumors from TCGA (Aim 1). We present strong preliminary results demonstrating that our approach works. As part of this aim, we will also perform a more focused investigation of known variants that have been robustly associated with immune-related phenotypes. Next, we will evaluate whether newly identified loci associated with tumor immune profile are contributing to colorectal cancer (CRC) risk and survival outcomes (Aim 2). To investigate this, we will leverage GWAS data from over 125,000 CRC cases and controls to examine association with cancer risk, and ~20,000 CRC cases to examine association with CRC disease-free and overall survival. The results yielded by this project will be among the first reporting germline genetic variants associated with tumor immune response, and colorectal cancer survival. Discoveries will have high translational potential. Not only will new findings contribute to improved understanding of the cellular and molecular basis of established associations between presence of TILs and clinical outcomes, new discoveries can also lead to improved prediction of treatment response, and may suggest new drug targets to promote immunity in immunotherapy nonresponders, and, ultimately, decrease cancer mortality.